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We have developed an in vitro protocol for the measurement of clot-bound thrombin. This protocol uses a chromogenic substrate for thrombin and a microtiter plate reader and is suitable for screening inhibitors for thrombin that are directed to clot-bound thrombin. Clots were obtained after recalcification of human plasma. For the measurement of clot-bound thrombin, we read the optical density (OD) at 405 nm on a spectrophotometer and compared the results to that obtained with a standard curve of human alpha thrombin. We stopped the amidolytic reaction at 10 min because the optical density was linear until 20 min under our experimental conditions. We suggest that clot-bound thrombin can be measured using a chromogenic substrate specific for thrombin under our experimental condition. [Copyright &y& Elsevier]

• Poly(acrylic acid) (PAA) is an inexpensive, nontoxic, durable, negatively charged material. • PAA supports factor XII autoactivation and thrombin generation in plasma. • PAA-impregnated filter paper reduces blood loss by 22 to 40% in two murine bleeding assays. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase inhibitors (CDKIs) may increase the risk of thrombotic events of endocrine therapy (ET) in women with hormone-sensitive, HER2-negative advanced breast cancer (BC). Aim of our systematic review is the estimate of the risk of venous and arterial thromboembolism in women with advanced BC treated with CDKIs in phase III randomized controlled trials (RCTs). Studies were identified by electronic search of MEDLINE, EMBASE and CENTRAL database until October 2021. Risk of bias was assessed according to Cochrane criteria. Differences in thrombotic outcomes among groups were expressed as pooled odds ratio (OR) and corresponding 95% confidence interval (CI), which were calculated using both a fixed-effects and a random-effects model. Statistical heterogeneity was evaluated using the I2 statistic. We included 7 phase III RCTs (4415 patients) for a total of 15 papers (7 were the first published paper and 8 the follow-up papers). Reporting of thrombotic events was at high risk of bias. Women with advanced BC treated with CDKIs and ET had a two to threefold increased risk of venous thromboembolic event (VTE) compared to ET plus placebo arm [OR 2.90 (95% CI 1.32, 6.37; I2 = 0%) in the main papers and OR 2.20 (95% CI 0.93, 5.20; I2 = 49%) in the follow-up papers]. Women with advanced BC treated with CDKIs and ET had a non-significant mild increased risk of arterial thromboembolic event compared to ET plus placebo arm [OR 1.22 (95% CI 0.47, 3.18 I2 = 0%)]. CDKIs in combination with endocrine therapy are associated with a two to threefold higher risk of VTE in comparison to endocrine therapy alone in women with advanced breast cancer, while the risk of arterial events is still to be defined. • CDKIs in combination with endocrine therapy have completely changed the treatment strategy of ER positive, HER2 negative metastatic breast cancer. • CDKIs in combination with ET are associated with a two to threefold increased risk of VTEs in seven phase III RCTs (4415 patients) • Women treated with CDKIs should be aware of VTEs symptoms, oncologists should monitor their patients for VTEs during outpatients visits, and researcher should assess the potential benefit of thromboembolic prophylaxis in women with advanced BC treated with CDKIs judged at high risk of VTE. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is the leading cause of direct maternal mortality in high-income countries. We previously developed a risk prediction score for postpartum venous thromboembolism (VTE) in women without a previous VTE. In this paper, we provide further external validation and assess its performance across various groups of postpartum women from England. Cohort study using primary and secondary care data covering England. We used data from QResearch comprising women with pregnancies ending in live birth or stillbirth recoded in Hospital Episodes Statistics between 2004 and 2015. Outcome was VTE in the 6 weeks postpartum. Our predictor variables included sociodemographic and lifestyle characteristics, pre-existing comorbidities, and pregnancy and delivery characteristics. Among 535,583 women with 700,185 deliveries, 549 VTE events were recorded (absolute risk of 7.8 VTE events per 10,000 deliveries). When we compared predicted probabilities of VTE for each woman from the original model with actual VTE events, we obtained a C-statistic of 0.67 (95% CI 0.65 to 0.70). However, our model slightly over-predicted VTE risk for the higher risk women (calibration slope = 0.84; 95% CI 0.74 to 0.94). Performance was similar across groups defined by calendar time, socioeconomic status, age group and geographical area. The score performed comparably with the existing algorithm used by the UK Royal College of Obstetrician and Gynaecologists. Our model enables flexibility in setting new treatment thresholds. Adopting it in clinical practice may help optimise use of low-molecular-weight heparin postpartum to maximise health gain by better targeting of high-risk groups. • Blood clots are the leading direct cause of maternal death in high-income countries. • We developed a score to predict which women are most at risk of VTE post-childbirth. • This paper externally validates the score in UK women using the QResearch database. • The score performed well in subgroups defined by age, region and socioeconomic status. • This score enables the potential for targeted thromboprophylaxis of high-risk groups. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is associated with excess risk of cardiovascular and thrombotic events in the early post-infection period and during convalescence. Despite the progress in our understanding of cardiovascular complications, uncertainty persists with respect to more recent event rates, temporal trends, association between vaccination status and outcomes, and findings within vulnerable subgroups such as older adults (aged 65 years or older), or those undergoing hemodialysis. Sex-informed findings, including results among pregnant and breastfeeding women, as well as adjusted comparisons between male and female adults are similarly understudied. Adult patients, aged ≥18 years, with polymerase chain reaction-confirmed COVID-19 who received inpatient or outpatient care at the participating centers of the registry are eligible for inclusion. A total of 10,000 patients have been included in this multicenter study, with Brigham and Women's Hospital (Boston, MA) serving as the coordinating center. Other sites include Beth Israel Deaconess Medical Center, Anne Arundel Medical Center, University of Virginia Medical Center, University of Colorado Health System, and Thomas Jefferson University Health System. Data elements will be ascertained manually for accuracy. The two main outcomes are 1) a composite of venous or arterial thrombotic events, and 2) a composite of major cardiovascular events, defined as venous or arterial thrombosis, myocarditis or heart failure with inpatient treatment, new atrial fibrillation/flutter, or cardiovascular death. Clinical outcomes are adjudicated by independent physicians. Vaccination status and time of inclusion in the study will be ascertained for subgroup-specific analyses. Outcomes are pre-specified to be reported separately for hospitalized patients versus those who were initially receiving outpatient care. Outcomes will be reported at 30-day and 90-day follow-up. Data cleaning at the sites and the data coordinating center and outcomes adjudication process are in-progress. The CORONA-VTE-Network study will share contemporary information related to rates of cardiovascular and thrombotic events in patients with COVID-19 overall, as well as within key subgroups, including by time of inclusion, vaccination status, patients undergoing hemodialysis, the elderly, and sex-informed analyses such as comparison of women and men, or among pregnant and breastfeeding women. • Cardiovascular events, mainly thrombosis, have been widely reported in COVID-19. • Recent event rates are unknown, considering vaccination or COVID-19 therapies. • Limited data exist in vulnerable subgroups such as pregnant or breastfeeding patients. • The CORONA-VTE-Network study seeks to address several of such knowledge gaps. • This paper provides an evidence summary of prior studies and the current registry. [ABSTRACT FROM AUTHOR]

• COVID-19 had a major impact on Thrombosis Research. • The number of submitted papers in 2020 increased by 150% compared to 2019. • Thrombosis Research published 100 papers on COVID-19 in 2020. • Number of downloads and citations of published papers increased considerably. • The Editors thank our reviewers and the editorial assistance offered by Elsevier. [ABSTRACT FROM AUTHOR]

Several studies agree that high socioeconomic position is protective against risk of PE. However, socioeconomic impact on outcomes from PE is not known. In this paper we aimed to compare differences in risk of recurrence and mortality within the first year following a first-time PE across level of education. Using Danish national registers, patients ≥18 years of age hospitalized with a first-time PE between 1998 and 2018 were registered. Based on International Standard Classification of Education system 2011 patients were divided into four levels of education. Risk of recurrence and death across educational level were assessed by cumulative incidence curves and multivariable adjusted absolute risk regression analyses. In total, 22,708 patients with basic education (60 % women, median age 73 years), 19,809 with high school/vocational education (43 % women, median age 67 years), 7257 with short/medium higher education (54 % women, median age 65 years) and 2410 with long higher education (34 % women, median age 64 years) were hospitalized for PE. Risk of recurrence was not influenced by increasing educational level (relative absolute risk (RAR) 0.97, [95 % confidence interval (CI), 0.85–1.11], RAR 1.01 [95 % CI, 0.85–1.19], RAR 0.81 [95 % CI, 0.60–1.09]) compared to basic education, however, risk of death decreased with increasing level of education (RAR 0.93 [95 % CI, 0.90–0.96], RAR 0.88 [95 % CI, 0.83–0.92], RAR 0.83 [95 % CI, 0.76–0.89]). Significant educational differences exist in mortality following PE, warranting a need for socially differentiated efforts targeted towards patients with low educational status. [ABSTRACT FROM AUTHOR]

Factor V Leiden (FVL) is an inherited autosomal dominant condition that is identified in 20%-50% of patients with venous thromboembolic diseases and 5-8% of the population in Canada. People with FVL are often called hypercoagulable, and have a five-fold increase in the risk of venous thrombosis. There is a low prevalence of FVL among patients with fatal pulmonary embolism (PE) and a higher incidence of deep vein thrombosis (DVT) than PE in patients with FVL. This has been referred to as the FVL paradox in thrombosis. We wished to test whether FVL and normal patients are at the same risk of initial thrombus formation, expect FVL patients present with symptomatic DVT while normal patients do not present, because the small asymptomatic DVT in normal patients embolizes to become an asymptomatic PE. Therefore, to explain why patients with FVL are more likely to present with a DVT rather than a PE we will study DVT stability in FVL mice using a modification of our previously published mouse model of venous thrombus stability. Platelets were fluorescently labeled using CD41 fab fragments conjugated to an Alexa Fluor 488. DVT was induced using a ferric chloride saturated filter paper on the femoral vein of female mice. We chose conditions such that only a small thrombus developed in wild type (WT) mice, and then compared them to thrombi in FVL heterozygous (F5L/+) and FVL homozygous (F5L/L) mice. Intravital videomicroscopy recorded embolic events leaving the thrombus and the thrombus sizes every 10 minutes for 2 hours. Lungs were harvested sectioned and stained for presence of PE. Although thrombus size remained small in WT mice, it significantly increased over time in F5L/+ and F5L/L mice. The number of total and large embolic events, and the percent of thrombus that embolized was significantly decreased in F5L/+ and F5L/L mice compared to WT mice. Previously we have correlated increased large embolic events with increased PE burden. FVL mice had significantly reduced PE burden compared to WT mice. Mice with F5L had higher F1.2 levels than in WT, consistent with increased thrombin generation. This suggests that in noncarriers (reflected by WT), a minor insult initially resulting in a small DVT tends to remain small and asymptomatic, due to the embolization. Alternatively, the same insult in people with FVL (reflected by F5L/L) leads to thrombus growth due to less embolization and thus development of symptomatic DVT, but no PE. [ABSTRACT FROM AUTHOR]

Abstract Positive family history is known to be an independent risk factor for venous thromboembolic (VTE) that may or may not reflect an underlying hereditary disorder. However, there is no clear standardized definition of what constitutes a positive family history for VTE in children. We aimed to assess the current published definitions of positive family history as a risk factor for VTE in children and ascertain if any consensus exists. Methods We conducted a literature review through two major databases PUBMED and EMBASE (1969–June 2018). Three different search statements were used for each database to maximize the number of relevant results, giving rise to 1050 non-duplicated papers. Results Of the 1050 papers, 32 articles demonstrated 18 separate definitions on what constitutes a positive family history in paediatric studies. Variations in definitions were related to the closeness of kinship (first or second-degree relatives), whether thrombosis was provoked or unprovoked, the age of presentation of thrombosis in the kinship, and clinical vs. laboratory definition of positive family history. Of the definitions, 1st degree relative/s developing VTE at any age whether provoked or unprovoked was most commonly described. Conclusion: According to this literature review, the definition of a positive family history in paediatric populations is non-standardized amongst current published papers. To enable accurate comparisons across studies and improve clinical risk assessment, we therefore propose the need for a standardized definition of what constitutes a positive family history. Highlights • Positive family history is a known independent risk factor for venous thromboembolic. • There is no current consensus on the definition of family history as a risk factor in paediatric VTE. • We propose the need for a standardized definition of positive family history to improve risk stratification of paediatric VTE. [ABSTRACT FROM AUTHOR]

Introduction Venous thromboembolic events (VTE) occur in more than 5% of hospitalized patients with acute CMV infection. In immunocompetent patients, splanchnic vein thrombosis (SVT) and splenic infarction have been suggested to represent approximately half of the published cases of CMV-associated VTE. We performed a systematic review of the literature with the aim to describe epidemiology, clinical characteristics, treatment, and natural history of CMV-associated SVT in immunocompetent patients. Methods Studies were identified by a PubMed and Google Scholar electronic database search until January 2018. All published papers describing immunocompetent adults with SVT occurring concomitantly to an acute CMV infection were included. Results Forty-four patients with CMV-associated SVT were described in 38 papers. Twenty-three patients were male, mean age was 38.1 years (range, 17–68). Symptomatic SVT occurred in 31 patients, incidental SVT in 13 patients. In symptomatic SVT, an acute and severe onset with small bowel or splenic infarction required surgical treatment for resolution in 22.6% of cases. Anticoagulation induced both a favourable clinical outcome and a recanalization of SVT in more than 70% of the remaining cases. In incidental SVT, a favourable clinical outcome and a complete recanalization of SVT by anticoagulation were reported in more than 80% of cases. No patient with CMV-associated SVT died and no SVT recurrence was reported. Conclusions CMV-associated SVT has probably a favourable clinical course in most patients. Only future, well-designed, prospective studies with an adequate follow-up will allow to confirm the data of published cases. [ABSTRACT FROM AUTHOR]

The Chinese Haemophilia Individualized Prophylaxis Study (CHIPS), which was launched in 2016, reported a significant reduction in haemarthrosis over a one-year study. However, its long-term efficacy requires verification. This paper summarizes the clinical outcomes of 18 severe haemophilia A (SHA) patients who completed one year on the CHIPS and 3 more years of follow-up. Clinical follow-up was based on the CHIPS protocol (from July 2018 to July 2021). Escalation was based on index joint bleeding, and serial ultrasound (greyscale and colour Doppler) examinations of the index joints (both sides of the ankles, knees and elbows) were conducted every 6 months via a scoring system. A total of 18 SHA patients completed the 3-year study. Fifteen patients dropped out due to the financial crisis during the COVID-19 pandemic in China. The median age was 5.4 (range 4.3–6.9) years. A significant reduction in haemarthrosis was achieved, with mean annual bleeding rates reduced from 18.9 ± 2.8 to 1.7 ± 0.4 (p < 0.001), annual joint bleeding rates from 3.1 ± 0.7 to1.2 ± 0.3 (p < 0.028). 5 out of 8 target joint resolved. Sixteen doses were escalated. At study exit, the heterogeneous treatment outcomes of the SHA boys were 5 at step 4 (20–25 lU/kg, every other day), 10 at step 3 (15–20 IU/kg, 3×/week), 2 at step 2 (10–15 lU/kg, 3×/week) and 1 at step 1 (10–15 lU/kg, 2×/week). The mean FVIII consumption was 2964 IU/kg/year, with savings. The quality of life improved, with Canadian Haemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT, Chinese Version 2.0) scores ranging from 68.8 to 78.8. There was no change in the ultrasound score. Our follow-up data on the 18 SHA boys after completing one year on the CHIPS verify the long-term efficacy of the CHIPS for haemarthrosis reduction, joint health preservation, improvement in the quality of life of the boys and cost savings. • CHIPS achieved significant reduction in haemarthrosis over a one-year study. • Significant reduction in joint bleeding was observed in the follow-up 3 years. • No progression of arthropathy based on ultrasound was observed. • Individualized secondary prophylaxis leads to reduced bleeding in boys with severe haemophilia A. [ABSTRACT FROM AUTHOR]

Patients with cancer have increased risks of venous and arterial thromboembolism and/or atrial fibrillation, for which anticoagulation is commonly used. For these indications, three main types of anticoagulants are recommended or used: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and vitamin K antagonists (VKAs), all have different advantages and disadvantages. Drug-drug interactions (DDIs) with anticoagulation are often cautioned against by major guidelines, but evidence remains scarce regarding the best management approach for specific drug combinations, particularly with DOACs. Significant DDIs might affect the efficacy and safety of anticoagulants and/or anticancer therapies as well as other interfering medications, and more studies are needed. This paper will review the available evidence and guidelines on DDIs with anticoagulants, focusing on the cancer population whenever possible, and propose directions for future research. • Venous thromboembolism is associated with morbidity and mortality in cancer patients. • Anticoagulation is commonly used in cancer patients to prevent or treat thrombosis. • Drug-drug interactions might affect efficacy and safety of anticoagulants and anticancer therapies. • Future studies are needed on clinical outcomes with selected drug combinations. [ABSTRACT FROM AUTHOR]

This paper reviews the current evidence on the pathogenesis, clinical manifestations, diagnosis and management of cancer-associated non-bacterial thrombotic endocarditis (NBTE). NBTE is an underdiagnosed condition characterized by sterile valvular vegetations composed of platelets and fibrin which are susceptible to systemic embolization. Cancer is a leading cause of NBTE and should be excluded in NBTE cases without a clear etiology. Malignancies most frequently associated with NBTE are mucin-releasing adenocarcinomas of the lung, ovary, biliary system, pancreas, breast and stomach. NBTE carries a high risk of arterial thromboembolism, while cardiac valvular dysfunction is much less frequent. NBTE appears to be an important underdiagnosed cause of cancer-associated embolic stroke of undetermined source. Characteristics associated with cancer-associated NBTE include elevated D-dimer, visceral infarcts, cerebral infarcts in multiple vascular territories, transcranial doppler microembolic signals, disseminated cancer and adenocarcinoma histology. Transesophageal echocardiography is the diagnostic test of choice, and all suspected cases should be evaluated for the presence of elevated D-dimers and disseminated intravascular coagulation. Long-term anticoagulation with low molecular weight heparin should be strongly considered, and surgical intervention is usually not needed. Underlying cancer must be diagnosed swiftly (if previously undiagnosed) and anti-cancer treatment should be initiated as soon as possible. The paucity of data regarding all aspects of NBTE, and the severe clinical consequences of untreated NBTE, are an urgent call for future research. • Cancer is common in non-bacterial thrombotic endocarditis (NBTE) and should be excluded. • Undiagnosed NBTE is an important cause of cryptogenic cancer-associated embolic stroke. • Transesophageal echocardiography is the gold standard for diagnosing NBTE. • NBTE carries a high risk of arterial thromboembolism, including recurrent embolism. • Long-term anticoagulation with low molecular weight heparin should be strongly considered. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a frequent complication in cancer patients and is associated with significant morbidity, mortality, and burden on the health care system [1]. Previous studies have suggested an association between genetic mutations in solid tumors and VTE risk. MEDLINE and EMBASE databases were searched from inception to February 2021. We aimed to include studies presenting data on VTE and genetic mutations with >5% frequency in patients with melanoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and colon, gastric and ovarian cancers. Meta-analyses of proportions and size effects were conducted if possible. Of 682 eligible articles, we included 33 articles, of which 26 papers reporting on a total of 13,844 patients were included in the meta-analysis. The estimated proportions of VTE in lung cancer patients with EGFR, KRAS, and ALK mutations were 7.3, 18.2, and 30.6%, respectively, whereas for colon cancer with KRAS mutations was 13%. In NSCLC patients with EGFR, KRAS and ALK mutations the relative risk (RR) of VTE was 0.98 (0.81–1.18, P = 0.818), 1.24 (0.78–1.97 P = 0.358) and 1.70 (1.46–1.97, P < 0.001), respectively using a fixed-effects model. In patients with colon cancer and KRAS mutation, no significant increase in the VTE risk was observed according to the random-effects model, RR 1.31 (0.79–2.19, P = 0.285). In patients with NSCLC, the presence of ALK mutations was associated with a high proportion and RR of developing VTE. There was no significant increase in the risk of VTE in patients with colon cancer and KRAS mutations. [ABSTRACT FROM AUTHOR]

Human body functions exhibit a circadian rhythm generated in peripheral cells and synchronized by the suprachiasmatic nucleus (SCN), which mostly is entrained by the daily light/dark cycles. Activity, meals and posture are capable of interfering with the endogenous circadian rhythm of coagulation parameters. An increasing number of human disorders show a circadian component, and epidemiological studies find cardiovascular events to peak in the morning hours. The aim was to review the circadian rhythms impact on fibrinolysis and coagulation in healthy individuals and cardiovascular patients. A total number of 25 studies were identified where 8 enrolled cardiovascular patients with or without healthy individuals. Using a MeSH-search in MEDLINE PubMed. Only original peer-reviewed papers were included. Results showed substantial variance with respect to exhibition of circadian rhythms and/or peak/trough times. Circadian rhythms of fibrinolysis were less pronounced in cardiovascular patients than in healthy individuals with decreased levels in the morning hours compared to healthy inducing higher risk of blood clotting. Because of small studied group sizes and failure to control for entraining factors, larger studies are needed to fully establish the effects of the circadian rhythm on especially coagulation. The findings of chronobiologic rhythms in coagulation and fibrinolysis could suggest a need for a chrono-pharmacological approach when treating/preventing cardiovascular diseases. • Risk of cardiovascular events peak in the morning pointing to a circadian factor • Diurnal thrombosis appears to be disturbed in cardiovascular patients. • Trend toward lower fibrinolysis in the morning hours in cardiovascular patients • Antithrombotic medication in the evening may be the best protective therapy [ABSTRACT FROM AUTHOR]

Pancreatic cancer is associated with a high risk of venous thromboembolism (VTE). However, comprehensive data on incidence, timing and relevant determinants of VTE in this particular population are scarce. Current study assesses incidence, timing and predictors of VTE in pancreatic cancer through different phases of disease. All pancreatic cancer patients treated in our tertiary referral center between 2013 through 2017 were studied. Occurrence of VTE was evaluated from diagnosis through end of follow-up or death. Relevant determinants of VTE were identified in logistic regression models. Hazard ratios were calculated to evaluate impact of VTE on overall survival. In total, 361 patients were followed for a median period of 43 months; 64 were diagnosed with VTE (18%). Most were tumor related thrombosis (59%), incidental (75%) and occurred after anti-cancer treatment had been stopped (80%), only 1.6% occurred during remission phase. Stage IV pancreatic cancer was a predictor for VTE (hazard ratio (HR) 2.46, 95% confidence interval (CI) 0.9–6.8). Biliary drainage (HR 0.52, 95%CI 0.28–0.98) and tumor resection (HR 0.45, 95%CI 0.45–1.83) were protective factors. VTE was not associated with worse survival (HR 1.3; 95% CI 0.97–1.74). VTE in pancreatic cancer is disease-stage dependent, with 80% occurring in advanced phases of disease when patients no longer receive active treatment. We speculate that this is the main reason for the absence of a survival effect of VTE in our cohort. These practice-based findings should be taken into account when considering wide-spread introduction of primary thromboprophylaxis in patients with pancreatic cancer. 'What is known on this topic' • Pancreatic cancer is among the most prothrombotic malignancies • There are ongoing discussions on the introduction of prophylactic anticoagulation in cancer patients 'What does this paper add' • A detailed overview of different types of VTE in all stages of pancreatic cancer • Tumor location, age and stage are predictors for development of VTE • 80% of all VTE occurs in the advanced disease phase. It is therefore debatable whether prophylactic anticoagulation is beneficial for this patient population [ABSTRACT FROM AUTHOR]

Coagulation and inflammatory parameters are mildly altered in children with SARS-CoV-2 (COVID-19) infection, and laboratory evidence of a proinflammatory and procoagulant state has been noted in multisystem inflammatory syndrome in children (MIS-C). It is not clear whether this pediatric condition is related to thrombotic events. With this study we reviewed the literature for thrombotic complications in children with COVID-19 infection and MIS-C. We searched the Medline PubMed Advanced Search Builder, Scopus, Web Of Science, and Google Scholar electronic databases (until 1 January 2021) using the medical subject headings (MeSH) terms and text words (their combinations and truncated synonyms): (THROMBOSIS OR THROMBOPHILIA) AND (CHILD OR CHILDREN OR INFANT) AND (COVID-19 OR SARS-CoV-2). Inclusion criteria were children with COVID-19 or SARS-COV-2 infection. The search was limited to articles published in English. Exclusion criteria were: reviews of published studies, studies published only as abstracts, letters or conference proceedings, discussion papers, animal studies, or editorials. After screening for duplicates, the initial search yielded 86 records: 12 were case reports involving 19 children; comorbidities were absent or mild in 73.7%. The most common site of thrombosis the lung (21%); the most often used drug was heparin (42%). Two studies were an international survey (n = 337 patients) and a large multicenter study (n = 186 patients with MIS-C). The risk of ischemic stroke in SARS-CoV-2 infection (0.82%) and deep venous thrombosis in MIS-C (4.3%) was lower in children than in adults. Thrombodic or thromboembolic events are rare in pediatric patients with COVID-19 infection and MIS-C. Nonetheless, as in adults, a high index of suspicion should be maintained in children with COVID-19 infection or MIS-C, particularly in those with comorbidities predisposing to thrombotic events. • MIS-C is characterized by laboratory evidence of a procoagulant state. • It is not clear whether MIS-C is related to thrombotic events. • Thrombotic events are rare in children with COVID-19 infection or MIS-C. • High index of suspicion for thrombotic events should be maintained in childhood. [ABSTRACT FROM AUTHOR]

Oral anticoagulant (OAC) intervention trials have typically included clinical event outcomes. However, there is no standard list of outcomes to be used in OAC research. This study aimed to describe and classify the outcomes used in recent prospective clinical studies involving OACs. We searched MEDLINE, EMBASE, and CINAHL databases from January 2009 to July 2019 for prospective studies with an intervention or control group that included one or more oral anticoagulants. We abstracted details about each included study and the outcomes used from the study report and its accompanying protocol. Using the Core Outcome Measures in Effectiveness Trials (COMET) Initiative recommendations, we categorised each outcome into one of five domains (mortality/survival, physiological/clinical, life impact, resource use, and adverse events). Our primary outcome was the prevalence of use of an outcome domain across studies. We included 70 prospective studies, including 52 randomized controlled trials and 18 prospective cohort studies. A total of 121 different outcomes were reported. The COMET domains were represented in the 70 studies as follows: mortality (63/70, 90.0%); physiological/clinical domain (70/70, 100%), life impact domain (43/70, 61.4%), resource use domain (26/70, 37.1%), and adverse events domain (55/70, 78.6%). Outcome reporting in prospective studies of OACs more frequently concentrates on mortality, physiological/clinical domains, and adverse events compared to life impact and resource utilization domains, the latter uncommonly used. A priority for future research includes developing a core outcome set (COS) for OAC research that represents all domains. • No standard list of outcomes to be used in oral anticoagulants research • Most papers having mortality, physiological/clinical, and adverse events domains • Fewer outcomes measured in the life impact and resource use domains • Provide information useful for developing COS for oral anticoagulants research [ABSTRACT FROM AUTHOR]

A Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) has become a pandemic disease named Coronavirus Disease-19 (COVID-19) of epochal dimension. The clinical spectrum of COVID-19 is wide, ranging from asymptomatic forms to severe pneumonia, sepsis and multiple organ dysfunction syndromes resulting in poor outcomes. Among the various consequences of severe COVID-19, cardiovascular (CV) collapse appears the most serious and potentially lethal. On the other hand, pre-existent CV comorbidities are also associated with higher mortality. The most reliable hypothetical pathogenetic mechanism for CV complications and cardiac injury in severe COVID-19 patients appears to be a sustained endothelial dysfunction, caused by the interplay of inflammation and coagulation. In this review, we survey papers addressing issues related to severe COVID-19, characterized by enhanced lung microvascular loss, hypercytokinemia, hypoxemia and thrombosis. We discuss about how the virus-induced downregulation of the angiotensin converting enzyme-2 (ACE2) receptor, used to enter the host cell, could affect the renin-angiotensin system, attempting to clarify the doubts about the use of ACE inhibitors and Angiotensin-II receptor blockers in COVID-19 patients. Finally, we point out how the delicate and physiological homeostatic function of the endothelium, which turns into a disastrous battlefield of the complex interaction between "cytokine and coagulative storms", can be irreparably compromised and result in systemic inflammatory complications. • Cardiovascular (CV) collapse appears the most serious consequence of severe COVID-19. • Endothelial dysfunction as pathogenetic mechanism for (CV) complications in COVID-19 patients • Hyperinflammation, immune dysregulation, hypoxia may drive vascular damage in COVID-19 patients. • Hypercoagulability state characterizes patients with severe COVID-19. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous thrombosis. Due to their novelty, pharmacokinetic DOAC drug-drug interactions (DDIs) that result in clinical adverse events have not been well-documented. This study aims to systematically review reported pharmacokinetic DDIs resulting in clinical adverse events through documented observational evidence to better inform clinicians in clinical practice. A comprehensive literature review of EMBASE, MEDLINE, and Ovid HealthStar was conducted through March 10th, 2020. Two independent reviewers screened and extracted data from eligible articles according to pre-established inclusion and exclusion criteria. Articles reporting bleeding or thrombotic outcomes in non-controlled (observational) settings resulting from suggested pharmacokinetic DOAC DDIs were included. A total of 5567 citations were reviewed, of which 24 were included following data extraction. The majority were case reports (n = 21) documenting a single adverse event resulting from a suspected DOAC DDI, while the remaining papers were a case series (n = 1) and cohort studies (n = 2). The most commonly reported interacting drugs were amiodarone and ritonavir (bleeding), and phenobarbital, phenytoin, and carbamazepine (thrombosis). Bleeding events more often resulted from a combined mechanism (P-glycoprotein AND CYP3A4 inhibition), whereas thrombotic events resulted from either combined OR single P-glycoprotein/CYP3A4 induction. Current literature evaluating the real-world risk of DOAC DDIs is limited to few case reports and retrospective observational analyses. Clinicians are encouraged to continue to report suspected drug interactions resulting in adverse events. • Patients on direct oral anticoagulants (DOACs) can encounter drug interactions. • Drug interactions can alter the amount of DOAC in a patient's system. • Research on DOAC interactions is currently limited and larger studies are required. • Health providers should continue to be cautious with potential DOAC interactions. [ABSTRACT FROM AUTHOR]

The value of D-dimer testing for the diagnosis of thrombosis in unusual sites is not properly established and evidence is scarce. We performed a systematic review of the literature. The search was conducted in MEDLINE and Cochrane Library for papers published in the last 10 years including different presentations of thrombosis in unusual sites. Twenty-three articles were included, from January 1, 2008, to December 31, 2018, comprising 3378 patients with thrombosis in unusual sites (upper extremity deep vein thrombosis, cerebral vein thrombosis and splanchnic vein thrombosis). The Newcastle-Ottawa scale was used to assess the quality of the studies. Two articles were related to upper extremity thrombosis, showing a high sensitivity and negative predictive value for D-dimer testing. Twelve articles concerned cerebral vein thrombosis, concluding that the timing of D-dimer testing was important, and that patients with a shorter duration of symptoms showed higher D-dimer levels. Sensitivity and specificity in these patients ranged from 58% to 97% and from 77% to 97.5%, respectively. Nine articles were related to splanchnic vein thrombosis. One described a population of patients with mesenteric venous thrombosis, and the rest included patients with portal vein thrombosis. The D-dimer testing methods and the proposed cut-off levels were remarkably different among the included studies. D-dimer testing should not be currently recommended for the diagnosis of thrombosis in unusual sites as a first line diagnostic tool. The development of algorithms combining biomarkers such as D-dimer and clinical decision tools could improve the diagnosis. • D-dimer testing for the diagnosis of venous thrombosis in unusual sites is controversial. • Upper extremity, cerebrum and abdomen are unusual sites of venous thrombosis. • There is the need for the standardization in D-dimer tests and cutoff levels. • D-dimer combined with a clinical decision rule may be useful for the diagnosis of upper extremity deep vein thrombosis. • The usefulness of D-dimer is still debatable in cerebral vein thrombosis and splanchnic vein thrombosis. [ABSTRACT FROM AUTHOR]

In this paper we tested a group of 66 healthy volunteers in terms of the influence of circadian rhythm on selected parameters of the coagulation system and fibrinolytic system. Blood was collected at 6-hour intervals, at 8 am, 2 pm, 8 pm and 2 am. Circadian variability was observed in the coagulation system parameters as well as in the fibrinolytic system. We observed increased platelet aggregation, APTT prolongation, along with increased levels of factors (fibrinogen, PAI-1) and PAP and TAT complexes that influence coagulation and fibrinolysis systems, in the blood samples collected in the morning (8 am). We also demonstrated a circadian rhythm in the number of circulating platelets (PLT), with a peak in the afternoon (2 pm) accompanied by increased concentrations of t-PA, D-dimers and PT prolongation. Based on the obtained results it was possible to conclude that circadian rhythm had an influence on the activation of coagulation processes in the morning, with a progressive activation of fibrinolysis up to the afternoon. Our results may be helpful in determining the transient risk of cardiovascular events, including myocardial infarction and ischemic stroke, and hence, can contribute to the effective prevention of such events. Such observations may also become a starting point of departure for further studies aimed at determining the circadian effect of secretion of parameters in the hemostasis system on the other systems and parameters in the human body. • Circadian rhythm had an influence on the activation of hemostasis processes. • Activation of coagulation system is accompanied by the activation of fibrinolysis system progressing from the morning hours to the afternoon hours. • Some of examined parameters in the circadian rhythm were differed between sexes. [ABSTRACT FROM AUTHOR]

Eponyms are honorific terms ascribed to individuals who discovered a sign, test, syndrome, technique, or instrument. Despite some contentions, eponyms continue to be widely ingrained and incorporated into the medical literature and contemporary language. Physical signs are considered unreliable methods alone for detecting deep venous thrombosis (DVT). The accuracy of the majority of these signs is unknown. For those signs that have been studied, there are a number of methodological limitations hindering the ability to draw meaningful conclusions about their accuracy and validity in clinical practice. Nevertheless, some findings when present and used in conjunction with other key signs, symptoms, and aspects of the patients history may be useful in further supporting the clinical suspicion and likelihood of DVT and/or pulmonary embolism (PE) or venothromboembolism (VTE). These signs also provide the means to better recognize the relationship between clinical findings and VTE. The acquisition of historical knowledge about these signs is important as it further enhances our understanding and appreciation of the diagnostic acumen that physicians were required to employ and to diagnose VTE prior to the advent of advanced imaging methods. Described in this paper is a brief overview of thrombosis as enumerated by Rudolf Virchow, and eponymous signs described in the late eighteenth and nineteenth centuries. • Physicians prior to Virchow established the groundwork for thrombosis. • Virchow described thrombosis occurring within the pulmonary artery. • Hampton and Westermark signs have a high specificity. • Homans sign has a wide sensitivity and specificity and high false positive rate. • Eponyms are a unique component of medical education. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The use of oral anticoagulant therapy is increasing in children. Managing anticoagulant therapy in children presents unique challenges, including poor venous access. The advent of point-of-care (POC) monitoring of anticoagulant therapy offers a potential solution to this challenge. This paper reviews the published literature relating to POC monitoring of oral anticoagulant therapy in children. Materials and methods: A Medline search was conducted and identified key publications. Papers were reviewed with respect to their objectives, populations and POC device investigated. Study limitations were identified. Results: Five publications and one abstract were identified, reporting studies using five different POC monitors. Three studies had a strong clinical management focus. Outcome measures assessed included target therapeutic range achievement and frequency of adverse events. Correlation between POC and laboratory-based results ranged from 0.83 to 0.96. Home monitoring and self-management using POC monitors were both reported to be preferred compared to standard laboratory testing. Conclusions: POC monitoring of oral anticoagulant therapy in children offers considerable advantages. The reviewed literature would suggest such monitoring can be performed accurately and reliably. The impact of quality control issues, such as calibration of thromboplastin ISI in POC devices, has not been explored in a paediatric population. Further studies are needed to clarify such issues and confirm the safety, reliability and efficacy of POC monitoring of oral anticoagulant therapy in children, including its home monitoring and self-management programs. [Copyright &y& Elsevier]

Abstract: In this paper, we will give an overview of the background for the possible effects of long-chain marine n-3 (synonomously called omega-3) polyunsaturated fatty acids (PUFA) in coronary heart disease (CHD) with focus on recent findings. In a forthcoming paper [Schmidt EB, Arnesen H, Christensen JH, Rasmussen LH, Kristensen SD, De Caterina R, Marine n-3 polyunsaturated fatty acids and coronary heart disease: Part II. Clinical trials and recommendations. Thromb Res (in press)], we will focus on the clinical trial data, current recommendations and suggest trials to further study the role of marine n-3 PUFA in the prevention and treatment of CHD. [Copyright &y& Elsevier]

Abstract Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y 12 inhibitors on thrombus stability and endogenous fibrinolysis are largely unknown. Blood taken from patients pre- and post-aspirin (n = 20) and on aspirin alone and on dual antiplatelet therapy comprising aspirin plus clopidogrel (n = 20), ticagrelor (n = 20) or cangrelor (n = 20), was tested using the Global Thrombosis Test. The number of "rebleeds" or drops (D) after early platelet-rich thrombus formation (occlusion time, OT), and before final lasting occlusion, was used as an inverse measure of thrombus stability. Whilst clopidogrel had no effect, ticagrelor and cangrelor both increased D significantly, reflecting increased thrombus instability [D pre- and post-clopidogrel 4.3 ± 1.6 vs. 4.5 ± 1.4, p = 0.833; pre- and post-ticagrelor 4.1 ± 2.4 vs. 6.8 ± 5.1, p = 0.048; pre- and post-cangrelor 3.6 ± 2.0 vs. 7.9 ± 8.9, p = 0.046]. Platelet reactivity was reduced by all P2Y 12 inhibitors, demonstrated by OT prolongation (clopidogrel 378 ± 87 s vs. 491 ± 93 s, p < 0.001; ticagrelor 416 ± 122 s vs. 549 ± 121 s, p < 0.001; cangrelor 381 ± 146 s vs. 613 ± 210 s, p < 0.001). The magnitude of OT prolongation compared to baseline (ΔOT) was significantly greater for cangrelor compared to clopidogrel and ticagrelor. Cangrelor was the only agent to enhance fibrinolysis (lysis time pre- and post-cangrelor 1622[1240–2048]s vs. 1388[960–1634]s, p = 0.005). We demonstrate the ability to assess the effect of pharmacotherapy on thrombus stability in vitro and show that P2Y 12 inhibitors potentiate thrombus instability at high shear. Cangrelor, and to a lesser extent ticagrelor, de-stabilised thrombus formation and cangrelor also enhanced fibrinolysis. Potentiation of thrombus instability could become a new pharmacological target, that may be particularly important in acute coronary syndromes. Highlights What is known on this topic • Thrombus stability, the ability to withstand embolization and fibrinolysis, is an important determinant of infarction • Prior studies of thrombus stability with perfusion chambers utilise citrated blood which inhibits the effect of thrombin • The effects of P2Y 12 inhibitors on thrombus stability and endogenous fibrinolysis are largely unknown • Antithrombotic agents have shear-dependent effects and may increase thrombus fragility or enhance endogenous fibrinolysis What this paper adds • P2Y 12 inhibitors affect thrombus stability under high shear, in non-citrated blood, using a point-of-care technique • Clopidogrel, ticagrelor and cangrelor, with aspirin, but not aspirin alone, inhibit shear-induced platelet reactivity • The magnitude of effect is greatest for cangrelor, followed by ticagrelor, and clopidogrel • Cangrelor and ticagrelor significantly de-stabilize thrombus formation and cangrelor also enhanced endogenous fibrinolysis • Potentiation of thrombus instability could become a new pharmacological target, particularly in acute coronary syndromes [ABSTRACT FROM AUTHOR]

Abstract The Fontan procedure has transformed the lives of children born with single-ventricle physiology, previously deemed inoperable. Worldwide, there are an increasing number of children with Fontan circulation, with the potential for survival into adulthood. Due to the abnormal circulation, Fontan patients have an increased risk of thromboembolic (TE) events, with up to 25% of events leading to death. Despite the importance of preventing TE events in this patient population, there is currently no clinical consensus on the optimal monitoring, thromboprophylaxis therapies, and treatment of these events. This paper reviews the available literature regarding anticoagulation in the pediatric and adult Fontan population, including the mechanisms for thrombosis and current antithrombotic therapies. Highlights • The Fontan procedure is the definitive palliation for babies born with single ventricle physiology • Refinements in surgery and peri-operative care has meant there is a growing population of people living with a Fontan • Fontan patients are at an increased risk of develop thromboembolism due to a multitude of factors • Thromoboprophylaxis with aspirin or warfarin is usually recommended however evidence for efficacy is limited [ABSTRACT FROM AUTHOR]

Background The prevalence of calreticulin (CALR) mutations in splanchnic vein thrombosis (SVT) varies among studies. The role of routine screening for CALR mutations in SVT patients remains a debate. Aim To synthesize the prevalence of CALR mutations according to the different types (i.e., Budd-Chiari syndrome [BCS] and portal vein thrombosis [PVT]) and characteristics (i.e., with and without myeloproliferative neoplasms [MPNs] and JAK2V617F mutation) of SVT patients. Methods Eligible studies were searched by the PubMed and Embase databases. The study quality was assessed according to the STROBE checklist. The proportion of CALR mutations was pooled by using a random-effects model. The heterogeneity and publication bias were calculated. Results Eleven papers were included. The study quality was moderate to high. The pooled proportion of CALR mutations was 1.21%, 1.41%, and 1.59% in SVT, BCS, and PVT patients, respectively; 1.52%, 1.03%, and 1.82% in these patients without JAK2V617F mutation, respectively; 3.71%, 2.79%, and 7.87% in these patients with MPN, respectively; and 15.16%, 17.22%, and 31.44% in these patients with MPN but without JAK2V617F mutation, respectively. Only the meta-analysis examining the prevalence of CLAR mutations in BCS patients with MPN but without the JAK2V617F mutation showed statistically significant heterogeneity. Statistically significant publication bias was seen only in the meta-analysis examining the prevalence of CALR mutations in SVT patients without the JAK2V617F mutation. Conclusion Screening for CALR mutations may have a role in SVT patients with a high probability of MPN in whom the JAK2V617F mutation has been excluded. [ABSTRACT FROM AUTHOR]

Post-thrombotic syndrome (PTS) is the most common long-term complication after deep vein thrombosis (DVT) developing in up to 70% of the patients. PTS is diagnosed on the basis of typical symptoms and signs of the lower limb with a previous DVT, but no objective diagnostic test exists. A number of diagnostic scales have been developed primarily for research purposes. An optimal diagnostic test for PTS should be reliable and easy to use, sensitive and specific, able to grade PTS severity, and to identify changes over time. We have identified reports on seven diagnostic scales that have been used for the diagnosis of PTS; the Widmer classification, the Clinical-Etiological-Anatomical-Pathological (CEAP) classification, the Venous Clinical Severity Score (VCSS), the Brandjes scale, the Ginsberg measure, the Villalta scale, and the Patient-reported Villalta scale. The aim of this paper was to review and present the existing diagnostic scales for PTS in adults and their utility in clinical studies. [ABSTRACT FROM AUTHOR]

Background Pediatric hospital-acquired venous thromboembolism (HA-VTE) rates have increased dramatically. To achieve generalizable knowledge in the derivation and validation of HA-VTE risk factors and risk prediction models and inform future risk-stratified prevention strategies, multi-institutional studies are needed. Objectives This paper presents an investigator-initiated, multicenter pediatric case-cohort study designed to identify risk factors for HA-VTE to create a HA-VTE risk prediction model. Methods A registry, which houses pertinent variables from HA-VTE subjects and non-HA-VTE controls, was created for the Children's Hospital-Acquired Thrombosis (CHAT) study. Specific variables from the registry associated with HA-VTE risk will be identified using multivariable regression to create a pediatric HA-VTE risk prediction model to be prospectively validated. Results Seven large pediatric institutions have entered over 600 HA-VTE subjects aged 0–21 years of age into the registry. Subjects showed a male predominance (57%), a median age of three years (IQR 0.3–13) and were most likely admitted to an intensive care unit (57%) at VTE diagnosis. Median time to HA-VTE was 10 days after admission. The most prevalent risk factors include central venous catheters (80%), surgery (43%), systemic steroids (31%), congenital heart disease (27%), infection (14%) and cancer (13%). Conclusions CHAT, with its creation of a risk prediction model with prospective validation using the CHAT registry, is a novel study design and will be the first step in identifying safe and effective strategies to decrease HA-VTE in children by helping define the highest risk population for initial, or more aggressive, thromboprophylaxis efforts. [ABSTRACT FROM AUTHOR]

Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. Despite full anticoagulation during pregnancy and the postpartum period, women with AT deficiency may still be vulnerable to developing venous thromboembolism (VTE), including fatal events. There is limited guidance on the management of AT deficiency in pregnancy, including the role of AT concentrates. Following a comprehensive review of the state of the art with respect to recommendations and guidelines, our expert panel in maternal-fetal medicine, hematology and basic science reached consensus on key issues in the recognition and management of AT deficiency in pregnancy. This paper summarizes the state of the art and summarizes what we believe are best practices with special emphasis on a multidisciplinary approach involving obstetrics and hematology in the care of women with AT deficiency. [ABSTRACT FROM AUTHOR]

Introduction Aldosterone seems to influence the haemostatic system by several mechanisms and to increase the risk of thrombosis. The objective of this meta-analysis was to assess the impact of inhibition of the mineralocorticoid receptor due to the use of mineralocorticoid receptor antagonists (MRAs) on venous and arterial thrombosis, bleeding events and mortality. Materials and methods We systematically searched PubMed and EMBASE through August 1, 2014, without language restrictions. Randomised controlled trials (RCTs) that tested the effect of MRAs versus active control/no treatment and reported data on thrombotic or bleeding events or mortality in patients with common causes of secondary hyperaldosteronism were included. Results 20 published RCTs reported in 19 papers for a total of 17,610 patients met inclusion criteria. Of these, all reported data on mortality, 15 on cardiovascular mortality, 14 on thrombotic events and 12 reported data on bleeding events. No RCTs investigated patients with primary hyperaldosteronism. 19 RCTs were performed in patients with hypertension and heart failure. In general, the heterogeneity was low. No differences were observed in arterial thrombotic and bleeding events. Patients treated with MRAs had 20% lower odds of total mortality and 23% of cardiovascular mortality compared with controls (odds ratio (OR) 0.80, 95% confidence interval (CI) 0.73–0.87 and OR 0.77, 95% CI 0.70–0.85, respectively). Conclusion Inhibition of the mineralocorticoid receptor with MRAs in patients with hypertension and heart failure does not change the risk of myocardial infarction, stroke and bleeding events. Our meta-analysis confirms the favourable effects of MRAs on total and cardiovascular mortality. These data suggest that MRAs can be considered as safe regarding their effects on haemostasis in patients with hypertension and heart failure. [ABSTRACT FROM AUTHOR]

Background The immediate administration of oral antiplatelet therapy in the form of aspirin plus a P2Y12 inhibitor is the universally recognised standard of care for patients who present with acute myocardial infarction. Despite strong recommendations for their use, there are a paucity of data describing their onset of action and clinical efficacy during the short time frames from confirmation of diagnosis to reperfusion with primary percutaneous coronary intervention. Objectives To complete a systematic review evaluating the currently available evidence regarding the pharmacokinetic and pharmacodynamic activity of orally administered clopidogrel, prasugrel and ticagrelor during the acute phase of a myocardial infarction in relation to mechanical reperfusion with primary percutaneous coronary angioplasty. Methods We searched PubMed and EMBASE databases up to January 2016 using the terms outlined in our search strategy. Results Twelve papers were included in our final analysis; seven relating to pharmacodynamic studies, one to a pharmacokinetic study and four to pharmacokinetic/pharmacodynamic studies. Conclusion Our results indicate that despite the administration of oral P2Y12 inhibitors including newer more potent agents that should allow for greater and more consistent levels of platelet inhibition, the physiological state of ST segment elevation MI (STEMI) and the co-administration of opioid based analgesia are associated with a reduction in the degree of platelet inhibition achieved following their administration. [ABSTRACT FROM AUTHOR]

Introduction: Identifying risk factors and strategies for the prevention of deep venous thromboembolismin major orthopedic surgery has allowed the development of Clinical Practice Guidelines (CPGs). Currently, there is a gap between clinical practice and the implementation of the recommendations of CPGs. The purpose of this paper is to report the impact of the implementation of improvement strategies on adherence to venous thromboembolism (VTE) prophylaxis guidelines. Materials and methods: We defined 3 quality indicators to assess the adequate use of thromboprophylaxis according to CPGs. We obtained a baseline measurement and identified several barriers for adherence. Six improvement strategies to promote adherence to CPGs were designed and applied. A systematic monitoring of these indicators was performed in real time and a description of the data was completed for patients undergoing primary joint replacement of the hip, knee and shoulder, during February 2012 and August 2014. Results: Data from 773 patients were obtained. In the first trimester, the average of adherence was: 98.3% for medical order in the post-operative note, 60.3% for opportune administration and 67% for adherence to therapy at home. In the trimester, the rates of adherence were 100%, 95.7% and 100% respectively. Conclusions: Combined strategies for improvement of adherence to VTE prophylaxis is associated with higher compliance with clinical practice guidelines. [ABSTRACT FROM AUTHOR]

Type 1 von Willebrand disease (VWD) is transmitted mainly as a dominant trait - especially in forms involving von Willebrand factor (VWF) levels below 20 U/dL - and less frequently as a recessive trait. In the latter case, mutations at heterozygous level may be associated with type 3 carrier status, while mutations at homozygous or compound heterozygous level often coincide with type 3 VWD. Here we present a recessive, severe type 1 form as a distinct type of VWD. Eight patients with severe type 1 VWD belonging to 7 unrelated families were studied. They had VWF levels below 10 U/dL, FVIII higher than 10 U/dL, and a significantly lower than normal platelet VWF content. All patients were homozygous or compound heterozygous for the c.1534-3C>A VWF mutation, that simultaneously induces the skipping of exon 14, the activation of a cryptic splice site, and a normal VWF gene transcription. This means that one of the three different mRNA generated assures the synthesis of normal VWF. The probands' relatives who were heterozygous for the c.1534-3C>A mutation always had low platelet VWF levels, sometimes with circulating VWF levels within normal range. This finding confirms the utility of measuring platelet VWF content to identify an abnormal VWF synthesis. Because the c.1534-3C>A mutation impairs, but does not abolish normal mRNA processing, it may never cause type 3 VWD. We propose a model of severe recessive type 1 VWF defect associated with mutations that sporadically go undetected by the cells' molecular machinery, as the c.1534-3C>A VWF mutation. Bullet Points What is known about this topic? Type 1 VWD is transmitted mainly as a dominant trait. Recessive type 1 mutations at homozygous or compound heterozygous level are often associated with type 3 VWD, and at heterozygous level with type 3 VWD carrier status. What does this paper add? There are quantitative VWF mutations, such as c.1534-3C>A, that impair, but do not abolish normal mRNA processing. The c.1534-3C>A VWF mutation simultaneously induces the skipping of exon 14, the activation of a cryptic splice site, and a normal VWF gene transcription. The c.1534-3C>A mutation is the archetype of mutations that cause severe recessive type 1 VWD, but never type 3 VWD. Recessive, severe type 1 appears to be a distinct form of VWD. [ABSTRACT FROM AUTHOR]

Introduction: Von Willebrand disease (vWD) is the second least common hemostatic disorder in Malaysia, and it has a low prevalence. This study examined the underlying platelet thrombogenicity cascades in the presence of different formulations of chitosan-derivatives in vWD patients. This paper aimed to determine the significant influence of chitosan biomaterial in stimulating the platelet thrombogenicity cascades that involve the von Willebrand factor, Factor 8, Thromboxane A2, P2Y12 and Glycoprotein IIb/IIIa in vWD. Materials and Methods: Variable chitosan formulations of N,O-Carboxymethylchitosan (NO-CMC) and Oligo-Chitosan (O-C) were tested. Fourteen vWD subjects voluntarily participated in this study after signing informed consent forms. The patient's demographic profiles, family history, type of vWD, clinical symptoms and laboratory profiles were recorded and analyzed. Enzyme-linked immunosorbent assay, flow cytometry and Western blot tests were used to determine the level of the chitosan-adhered-platelet-mechanisms. Results: The study revealed that most patients were predominantly affected by vWD type I. The O-C group of chitosan's scaffold pores is sufficient to allow for nutrients and cells. The O-C-stimulated-mediators are capable of initiating the platelet actions and were detected to expedite the blood coagulation processes. The oligo-group of chitosans was capable of amplifying and triggering more platelet activator's pathways via the studied mediators. The present findings suggest that the ability of each type of chitosan to coagulate blood varies depending on its chemical composition. Conclusion: The oligo group of chitosans is potentially capable of triggering platelet thrombogenicity cascades by activating platelets in vWD patients to form a platelet plug for hemostasis process. [ABSTRACT FROM AUTHOR]

While antithrombotics are usually administered intravenously, subcutaneously or orally, there are a number of publications reporting topical application of anticoagulation therapy. This paper aims to review the available literature regarding clinical conditions, the details of the topical antithrombotic treatment, as well as positive or adverse effects in an attempt to ascertain the safety and efficacy of this form of treatment. Published literature was searched to identify publications reporting the use of antithrombotic treatments administered via topical application between 1st January1990 and 1st January 2013. There were 43 studies reported in 10 different clinical conditions. Majority of the studies were randomized controlled trials (51.2%), prospective studies (18.6%) or case reports (11.6%). The clinical conditions in which topical antithrombotics were administered included: microangiopathy, acute haemorrhoids, periodontitis, dermatitis, burns, ocular conditions and surgery, blunt force impact, scars, as well as clinical conditions associated with superficial venous thrombosis (SVT). The most commonly used topical antithrombotic was heparin (79.1% of studies). The respective dosage of different antithrombotics varied depending on specific clinical conditions. While most studies reported mean improvements or resolution of symptoms/condition in patients, the patient outcomes were variable. This review demonstrates that topical antithrombotic treatment is used according to a wide variety of protocols, with a subsequent variability in patient outcomes. Specific guidelines for the use of topical antithrombotics should be developed to standardize this form of treatment and ensure the best possible outcomes for patients. Highlights • There is a growing trend of administering antithrombotics topically. • We review the available literature regarding topical use of antithrombotics. • Topical antithrombotics are administered in a large variety of clinical settings. • The most commonly used topical antithrombotic is heparin. • Guidelines are needed to standardize this treatment and improve patient outcomes. [ABSTRACT FROM AUTHOR]

The brain and the placenta synthesize identical peptides and proteins, such as brain-derived neurotrophic factor, oxytocin, vascular endothelial growth factor, cortisol, and matrix metalloproteinases. Given the promiscuity between neurochemistry and the mechanism of placentation, it would be expected that mental disorders occurring during pregnancy would increase the risk of adverse obstetric and neonatal outcomes. Indeed, expectant mothers with anxiety disorders, post-traumatic stress disorder, schizophrenia, or depressive disorders are at higher risk of preterm birth, low-birth-weight and small-for-gestational-age infants than controls. These mental illnesses are accompanied by a procoagulant phenotype and low activity of tissue plasminogen activator, which may contribute to placental insufficiency. Another risk factor for pregnancy complications is hyperemesis gravidarum, more common among women with eating disorders or anxiety disorders than in controls. Severe hyperemesis gravidarum is associated with dehydration, electrolyte imbalance and malnutrition, all of which may increase the risk of miscarriages, of low-birth-weight babies and preterm birth. This paper reviews some aspects of mental disorders that may influence pregnancy and neonatal outcomes. [ABSTRACT FROM AUTHOR]

Background Thrombophilia is reported to be a candidate etiology of recurrent pregnancy loss (RPL). No conclusive results on the association between prothrombin G20210A mutation and RPL have been reported. Methods We undertook a systematic review and meta-analysis of 37 case-control studies using a comprehensive electronic search on papers published by May 2014. We studied 5400 cases and 4640 controls to investigate the potential association between G20210A and RPL. In this review, we define RPL as more than 2 miscarriages. Results A significant association was found between G20210A and RPL, with a combined odds ratio (OR) of 1.81 (95% confidence interval [CI]: 1.26-2.60). However, the risks differed in the subgroup analyses, categorized by study sites, maternal age, and type of miscarriages. The pooled OR remained significant in European studies (OR: 1.80, 95% CI: 1.35-2.41), whereas in the Middle-Eastern studies, it was not significant (OR: 2.39, 95% CI: 0.96-5.92). The risk of RPL was significantly higher in women older than 29years (OR: 1.91, 95% CI: 1.61-6.11), and a positive relationship was only observed between prothrombin G20210A mutation and fetal loss, but not embryonic loss. There was no evidence of publication bias in any of the analyses. The sensitivity analyses showed that the findings were quite stable. Conclusion This meta-analysis suggests that the G20210A prothrombin mutation increases the risk of RPL (fetal loss, primary RPL, or secondary RPL), particularly in Europeans and women older than 29years. We recommend further screening in more specific groups among women. [ABSTRACT FROM AUTHOR]

Thrombin is a key blood clotting enzyme; therefore, developing of its inhibitors has become a mainstream in antithrombotic pharmacology. As a result, a wide variety of proteins, peptides, peptidomimetics, DNA, RNA, and carbohydrates were reported to be effective inhibitors of thrombin activities. The majority of described inhibitors were characterized kinetically with amidolytic assay only; though some of them inhibit fibrinogen binding rather than amidolytic activity, e.g. hirugen and nucleic acid aptamers. Per contra, studying the inhibition kinetics of fibrinogen hydrolysis might reveal essential peculiarities of mechanism of action of thrombin inhibitors. In this paper the effect of thrombin inhibitors on fibrinogen hydrolysis has been investigated using improved turbidimetric assay. This technique is highly productive versus fibrinopeptide determination allowing elucidation of inhibition type and apparent constant for different types of thrombin inhibitors. The protein (recombinant hirudin, antithrombin III), peptide (bivalirudin, hirugen), and peptidomimetic (argatroban, PPACK) inhibitors were characterized in terms of inhibition types for the first time. Unexpectedly, for others: heparin, RNA aptamer Toggle-25t, partial inhibition has been shown indicating allosteric interplay between exosites. Improved turbidimetric assay is also applicable for studying the fibrin association inhibitors. Hence, GPRP-peptide was characterized kinetically for the first time. The kinetic study revealed a repertoire of different inhibition types and also close allosteric interplay within the thrombin. The results are undoubtedly important for understanding the enzyme activity regulation, as well as for the rational development of new antithrombotic substances. [ABSTRACT FROM AUTHOR]

Salvianolic acid B (SAB) is a hydrophilic component isolated from the Chinese herb Salviae miltiorrhizae, which has been used clinically for the treatment of ischemic cardiovascular and cerebrovascular diseases. Platelets-mediated vascular inflammatory response contributes to the initiation and progression of atherosclerosis. In this paper, we focus on the modulating effects of SAB on the inflammatory reaction of endothelial cells triggered by activated platelets. Human umbilical vein endothelial cells (EA.hy926) were pretreated with SAB followed by co-culture with ADP-activated platelets. Adhesion of platelets to endothelial cells was observed by amorphological method. The activation of nuclear factor-kappa B was evaluated by NF-κB p65 nuclear translocation and the protein phosphorylation. A determination of the pro-inflammatory mediators (ICAM-1, IL-1β, IL-6, IL-8, MCP-1) mRNA and protein were also conducted. In addition, the inhibitory effects of SAB on platelets activation were also evaluated using a platelet aggregation assay and assessing the release level of soluble P-selectin. The results showed that SAB dose-dependently inhibited ADP- or α-thrombin-induced human platelets aggregation in platelet rich plasma (PRP) samples, and significantly decreased soluble P-selectin release from both agonists stimulated washed platelets. It was also found that pre-treatment with SAB reduced adhesion of ADP-activated platelets to EA.hy926 cells and inhibited NF-κB activation. In addition, SAB significantly suppressed pro-inflammatory mediators mRNA and protein in EA.hy926 cells in a dose-dependent manner. These results indicated that, in addition to its inhibitory effects on platelets activation, SAB was able to attenuate platelets-mediated inflammatory responses in endothelial cells even if the platelets had already been activated. This anti-inflammatory effect was related to the inhibition of NF-κB activation. Our findings suggest that SAB may be a potential candidate for the treatment of various atherosclerotic diseases. [ABSTRACT FROM AUTHOR]

Objective Rofecoxib, a selective cyclo-oxygenase-2 (COX-2) inhibitor, has been associated with increased arterial thrombosis. It is unknown whether (COX-2) inhibition is associated with venous thromboembolism (VTE).We investigated, using a systematic review of the literature, the association between rofecoxib and venous thrombosis. Methods A search strategy was developed and implemented to identify all English language studies in which rofecoxib was compared with placebo, irrespective of the primary outcome of the study. Study methodology and results were reviewed in a standardized manner using RefMan software. Confidence intervals and risk difference were calculated using a Poisson distribution. Results The search strategy identified 1339 papers; 15 studies met our pre-specified inclusion criteria. The majority of trials were short in duration (~12weeks). All studies met at least two of the three quality criteria. In 15160 (9217 person years follow up) patients allocated to rofecoxib there were 8 VTEs reported, compared with 9 VTEs in 13147 (9092 person years) patients allocated to placebo (relative risk 0.87, 95% CI 0.29-2.56, p=NS). The estimated incidence of VTE was 86.8 per 100,000 (95% CI 37.5 -171.2) person years with rofecoxib, and 99.1 per 100,000 person years with placebo (95%CI 45.3 - 188). This difference is not statistically significant (p=0.78). Conclusions Our findings are limited by the relatively small number of events, although, the contributing sample size of 28307 subjects (18309 person years) is reasonable. From our best available data outlined in this manuscript, there is no increase in the risk of VTE with rofecoxib use. [ABSTRACT FROM AUTHOR]

Introduction Deep vein thrombosis (DVT) is a life-threatening complication in intensive care unit (ICU) patients and DVT incidence is used as a marker of quality care. In our ICU an educational program for implementation of DVT prophylaxis and ultrasound screening resulted in a remarkable decrease in DVT incidence which fell from 11.6% to 4.7%. The aim of this paper is to investigate a 4-year long persistent quality improvement of DVT prophylaxis obtained through the implementation of our educational intervention. Methods The study was composed of three phases: after the first retrospective investigation of DVT incidence and the evidence of the efficacy of the educational program, this third phase investigates the 2-year long sustainability and persistence in the fall of DVT incidence by the adoption of 1) an electronic form for DVT prophylaxis prescription, 2) a nursing protocol for the application of elastic stokes and 3) a personalized form with a check-list dedicated to DVT prophylaxis. Ultrasound DVT screening was performed twice a week by ICU clinicians. Results The application of DVT prophylaxis was associated with a very low incidence of DVT (2.6%) not entirely attributable to changes in characteristics of enrolled patients and/or to less intensive DVT ultrasound screening when compared to the preceding phases. Mean mechanical ventilation duration and ICU length of stay were short and similar to those of the second phase and ICU mortality did not change. Conclusions The direct involvement of ICU clinicians and nurses in the application of DVT prophylaxis and in DVT diagnosis markedly contributed to maintain a low DVT incidence over time, despite the high turnover of patients. Abbreviations ICU, Intensive Care Unit; DVT, Deep Vein Thrombosis; LMWH, Low Molecular Weight Heparin; CUS, Compressive UltraSonography; GES, Graduated Elastic Stocking; ECMO, Extra Corporeal Membrane Oxygenation; SAPS II, Simplified Acute Physiology Score II [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Cerebral ischaemia is associated with altered platelet and fibrin network ultrastructure indicating increased coagulation activity and resistance to fibrinolysis; which may lead to the occlusion of blood vessels. Recently, it has been shown that the addition of red blood cells to plasma has a significant effect on the structural and mechanical properties of fibrin clots and is associated with lytic resistance of thrombi. Materials and Methods: Whole blood was collected from pre-ischaemic control Sprague Dawley rats and those in which experimental cerebral ischaemia was induced by hyperglycaemic two-vessel occlusion, for the ultrastructural investigation of whole blood thrombi by scanning electron microscopy. Post-ischaemic groups were terminated at 2h, 24h and 48h subsequent to reperfusion; which were time points selected for the demonstration of initial inflammation upon neural injury, maximal neural injury and onset of regeneration. Results: Subsequent to ischaemic insult, red blood cells transformed from normal discoid shape to form projections which allowed them to interact both with each other and with fibrin fibres in various manners. Researches have in recent years shown that inclusion of red blood cells in experimental coagula results in delayed fibrinolysis and lytic resistance. This paper shows the morphological alterations at cellular level which may elucidate the structural and mechanical strength of these clots. Conclusions: Through the extension of projections, red blood cells become intertwined within a thrombus to stabilise and strengthen its structure. The tighter these mechanical bonds, the more resistant thrombi are to lysis, an established characteristic of thrombi in cerebral ischaemia. [Copyright &y& Elsevier]

Abstract: Introduction: Deep vein thrombosis (DVT) is one of the common complications of orthopedic surgery. Low molecular weight heparin (LMWH) is a usually used agent for DVT, but it would increase the risk of bleeding. LRRFIP1 has been shown to play an important role in the formation of thrombosis. Therefore, we investigated the effect of LRRFIP1 shRNA lentivirus on DVT in mice. Materials and Methods: Lentiviral Vectors carrying LRRFIP1 shRNA were constructed and transfected into cultured mouse bone marrow cells (BMCs). Male ICR mice were irradiated with a single dose of 9.5Gy and then were injected with different agents through the tail vein. Stasis venous thrombosis was induced by inferior vena cava (IVC) ligation. Mice were sacrificed on the 1st, 3rd and 7th day post operation and the thrombi were removed, blotted the excess blood on it with filter paper and immediately weighed. P-selectin and d-Dimer were determined by enzyme-linked immunosorbent assay (ELISA). Results: LRRFIP1 shRNA significantly suppressed the expression of LRRFIP1 in the thrombi. In contrast, low molecular weight heparin (LMWH) and negative shRNA exhibited little effect on the expression of LRRFIP1. LRRFIP1 shRNA, LMWH and negative shRNA inhibited the thrombus formation in vivo significantly. The plasma P-selectin and d-Dimer levels were significantly increased after IVC ligation. LRRFIP1 shRNA significantly decreased the plasma P-selectin and d-Dimer levels. However, LMWH and negative shRNA showed little effects on the levels of plasma P-selectin and d-Dimer. Conclusion: LRRFIP1 shRNA might represent a promising prevention strategy for DVT. [Copyright &y& Elsevier]

Abstract: Mechanisms involved in the relationship between hyperhomocysteinemia and hemostatic process are still unclear. In the literature there are few papers describing studies on the effects of homocysteine (Hcys) on proteins that participate in blood coagulation and fibrinolysis in human. The aim of our study was to establish and compare the influence of a reduced form of Hcys (at final doses of 0.01 – 1mM) and the most reactive form of Hcys – its cyclic thioester, homocysteine thiolactone (HTL, 0.1 – 1μM) on the clot formation (using whole human plasma and purified fibrinogen) and the fibrin lysis. Moreover, the aim of our study was to explain the effect of plasma protein modifications (S- and N-homocysteinylation) on selected parameters of hemostasis. We observed that HTL, like its precursor, a reduced form of Hcys stimulated polymerization of fibrinogen, but this process was not dose-dependent. In the presence of HTL (at the lowest tested concentration – 0.1μM) the increase was about 55%. Our present results also demonstrated that Hcys in the reduced form (0.01 – 1mM) and HTL at lower doses than Hcys (0.1 – 1μM) reduced the fibrin lysis in whole human plasma. Our results reported that HTL, like the reduced form of Hcys (at concentrations corresponding to concentrations in plasma during hyperhomocysteinemia) induced modifications of hemostatic plasma proteins, and the consequence of these modifications may be alteration in protein structure associated with changes of hemostatic functions. [Copyright &y& Elsevier]

Abstract: Background: This is the first paper reporting a performance verification study of a point-of-care (POC) monitor for prothrombin time (PT) testing according to the requirements given in chapter 8 of the International Organization for Standardization (ISO) 17593:2007 standard “Clinical laboratory testing and in vitro medical devices — Requirements for in vitro monitoring systems for self-testing of oral anticoagulant therapy”. The monitor under investigation was the new CoaguChek XS system which is designed for use in patient self testing. Its detection principle is based on the amperometric measurement of the thrombin activity generated by starting the coagulation cascade using a recombinant human thromboplastin. Methods: The system performance verification study was performed at four study centers using venous and capillary blood samples on two test strip lots. Laboratory testing was performed from corresponding frozen plasma samples with six commercial thromboplastins. Samples from 73 normal donors and 297 patients on oral anticoagulation therapy were collected. Results were assessed using a refined data set of 260 subjects according to the ISO 17593:2007 standard. Results: Each of the two test strip lots met the acceptance criteria of ISO 17593:2007 versus all thromboplastins (bias −0.19 to 0.18 INR; >97% of data within accuracy limits). The coefficient of variation for imprecision of the PT determinations in INR ranged from 2.0% to 3.2% in venous, and from 2.9% to 4.0% in capillary blood testing. Capillary versus venous INR data showed agreement of results with regression lines equal to the line of identity. Conclusion: The new system demonstrated a high level of trueness and accuracy, and low imprecision in INR testing. It can be concluded that the CoaguChek XS system complies with the requirements in chapter 8 of the ISO standard 17593:2007. [Copyright &y& Elsevier]

Abstract: Introduction: Enoxaparin is the current anticoagulant of choice for neonatal thrombosis. Present neonatal treatment guidelines of 1.5 mg/kg every 12 hours (q12 h) are extrapolated primarily from an earlier study with 9 infants less than 2 months of age. More recent studies indicate an increased dose requirement for neonates. Materials and methods: Relevant data from articles and abstracts were identified by searching MEDLINE and pediatric and hematology conference proceedings. Results: Publications between 1996 and 2007 included 8 papers, 4 abstracts and 1 review article with primary research documenting enoxaparin use in 240 neonates. The mean maintenance dose of enoxaparin ranged from 1.48 to 2.27 mg/kg q12 h for all infants, but was higher for preterm neonates at 1.9–2.27 mg/kg q12 h. The efficacy of enoxaparin, causing either complete or partial resolution was between 59 and 100%. Minor side effects were common and adverse events (major bleeding) occurred in 12 patients (0–19%). Conclusions: Increased experience with enoxaparin use in neonates in the past decade has indicated higher doses to achieve accepted target anti-factor Xa values. The long-term use of indwelling catheters (Insuflon® catheter) for enoxaparin administration may need to be reevaluated in ELBW infants. Suggested starting doses of enoxaparin are 1.7 mg/kg q12 h for term neonates and 2.0 mg/kg q12 h for preterm neonates if there is no considerable bleeding risk. However, further prospective studies are needed to validate an increased initial dose of enoxaparin. [Copyright &y& Elsevier]

Abstract: ADP plays a key role in platelet aggregation which has led to the development of antiplatelet drugs that target the P2Y12 receptor. The aim of this study was to characterize the effects of two novel P2Y12 receptor antagonists, BX 667 and its active metabolite BX 048, on platelets. BX 667 and BX 048 block the binding of 2MeSADP to platelets and antagonize ADP-induced platelet aggregation in human, dog and rat washed platelets. Both compounds were shown to be reversible inhibitors of platelet aggregation. BX 048 prevents the decrease in cAMP induced by treatment of platelets with ADP. The specificity of BX 667 and BX 048 was demonstrated against cell lines expressing P2Y1 and P2Y6 as well as against a panel of receptors and enzymes. Taken all together these data show that both BX 048 and BX 667 are potent P2Y12 antagonists with high specificity which, in the accompanying paper are demonstrated to behave predictably in vivo. [Copyright &y& Elsevier]